Project Summary/Abstract: In 2011, the National Lung Screening Trial (NLST) reported a 20% reduction in lung cancer mortality and a 6% reduction in all-cause mortality for participants screened with Low Dose CT (LDCT) as opposed to chest X-ray (CXR). Based largely on these findings, lung screening using LDCT is now available to 8.7 million people in the United States who meet the NLST eligibility criteria. For high-risk individuals younger than 65, insurance coverage is mandated under the Affordable Care Act; for those 65 and older screening is covered by Medicare. The area of the body imaged during LDCT lung screening encompasses more than the lung, and abnormalities are often visualized in other organs. Findings that are unrelated to lung cancer, but which are of potential clinical importance, are commonly referred to as significant incidental findings (SIFs). In the NLST, SIFs were detected in 10% of participants at the first screen and an average of 6% at each of the two incidence screens. Although SIFs are known to be associated with increased health care utilization, it remains unclear whether detection of these abnormalities is beneficial or detrimental to patient health. SIFs may prove beneficial if they represent potentially malignant conditions, such as cancers, for which early intervention improves outcomes. However, SIFs may prove harmful if they represent benign conditions, such as liver cysts, whose work-up causes additional morbidity, costs, or mental duress for patients. The outcomes associated with SIFs are likely to differ depending on the organ in which the SIF is discovered. The discovery of SIFs in the NLST may, in part, explain the difference in all-cause mortality reported between the LDCT and CXR arms. The goal of this project is to understand the morbidity and mortality associated with detection of a SIF on LDCT lung screening. Information on SIFs and short- and long-term outcomes is available in the NLST data, and offers a unique opportunity to determine the morbidity and mortality associated with LDCT- detected SIFs. We propose to use the NLST data to determine whether SIF detection was associated with reduced all-cause mortality in the LDCT arm of the NLST, compared with the CXR arm. We also plan to identify those SIFs most likely to lead to cancer detection, and those SIFs most often associated with iatrogenic complications. Findings from this study will provide evidence that may be used to develop practice guidelines that can be applied to the management of LDCT-detected SIFs to maximize the cost-effectiveness and health benefits of lung cancer screening programs and to minimize the potential harms.